Transplantable lymphoma cells, called reticulum cell sarcomas (RCS), from SJL mice induce strong proliferative responses and lymphokine production in syngeneic Lyl[unreadable]+[unreadable] 2[unreadable]-[unreadable] T cells but not in T cells from F[unreadable]1[unreadable] hybrid mice of SJL with strains expressing I-E. Thymus and lymph node cells from bone marrow chimeras of nonresponder F[unreadable]1[unreadable] into SJL respond as well as do SJL T cells and, conversely, T cells from SJL to F[unreadable]1[unreadable] chimeras fail to respond. It has been established that RCS cells do not express alien I-E-alpha chains, and monoclonal antibody to I-A[unreadable]S[unreadable] completely blocks T cell stimulation by RCS. Two-dimensional gel electrophoresis of labeled surface I-A show acidic A-alpha chains or RCS cells absent from normal SJL spleen cells but at least partially present on LPS-induced B-cell blasts. The molecular heterogeneity with respect to charge but not size is removed by treatment with neuraminidase, whereas tunicamycin-treated RCS and SJL spleen cell I-A molecules appear identical. Neuraminidase treatment enhances, while tunicamycin treatment abolishes, the ability of RCS to stimulate syngeneic T cells. Recently derived RCS-specific T cell clones respond to both RCS cells and to LPS-induced B cell blasts, but not to resting spleen cells from SJL or (SJL x BALB/c) F[unreadable]1[unreadable] hybrids and not to allogeneic (H2[unreadable]b[unreadable]) B cell blasts. The results to date suggest that the T cells which are stimulated by RCS, and whose response appears needed for RCS growth in vivo, are specific for activated B cell antigens, possibly glycosylated I-A molecules. These T cells may represent physiologically important autoreactive helper cells which, in SJL mice, are deregulated and promote growth of lymphomas of the B cell lineage. (LB)